Oxalate is the salt of a weak acid and is a metabolic end product that is excreted through the kidneys. A disrupted oxalate homeostasis in humans and animals can cause severe conditions due to the tendency of oxalate to damage the renal parenchymal cells both as free oxalate and as calcium-oxalate crystals; thus, in many cases causing irreversible damage. Oxalate homeostasis is severely disrupted due to inborn errors such as Primary Hyperoxaluria (PH).
Primary Hyperoxaluria (PH) is a rare autosomal recessive inborn error of the glyoxylate metabolism, with an incidence rate of 0.1-0.2 per million. PH type I is caused by deficient or absent activity of liver specific peroxisomal alanine/glyoxylate aminotransferase (AGT). In some patients, enzyme is present but mis-targeted to mitochondria where it is metabolically inactive.
PH type II occurs as a result of deficient glyoxylate reductase/hydroxypyruvate reductase (GRHPR) enzyme activity. Both types of PH are characterized by severe hyperoxaluria that is present from birth. Patients experience recurrent calcium-oxalate urolithiasis, nephrocalcinosis and progressive renal failure.
There are no approved therapies to treat the enzyme deficiency or enzyme dysfunction in either PH type I or PH type II. Current therapies for PH are directed to decrease oxalate production or to increase the urinary solubility of calcium oxalate in order to preserve renal function. Patients are given treatment with magnesium, citrate, and orthophosphate supplementation to increase the urinary solubility of calcium oxalate. Pyridoxine is a co-factor of the deficient AGT and pharmacological doses of pyridoxine may reduce urinary oxalate levels in a minority of patients with PH I. Eventually the only curative therapy is a combined kidney and liver transplantation.
Secondary Hyperoxaluria includes oxalate-related conditions such as, but not limited to, hyperoxaluria, absorptive hyperoxaluria, enteric hyperoxaluria, idiopathic calcium oxalate kidney stone disease (urolithiasis), vulvodynia, oxalosis associated with end-stage renal disease, cardiac conductance disorders, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and disorders/conditions caused by/associated with gastrointestinal surgery, bariatric surgery (surgery for obesity), and/or antibiotic treatment. Kidney/urinary tract stone disease (urolithiasis) is a major health problem throughout the world. Most of the stones associated with urolithiasis are composed of calcium oxalate alone or calcium oxalate plus calcium phosphate.
Kidney or urinary tract stone disease occurs in as many as 12% of the population in Western countries and about 70% of these stones are composed of calcium oxalate or of calcium oxalate plus calcium phosphate. Some individuals (e.g. patients with intestinal disease such as Crohn's disease, inflammatory bowel disease, or steatorrhea and also patients that have undergone jejunoileal or Roux-en-Y bypass surgery) absorb more of the oxalate in their diets than do others. For these individuals, the incidence of oxalate urolithiasis is markedly increased.
Oxalate homeostasis is a complex process, not yet completely resolved, including many different bodily organs and mechanisms. The mammalian kidneys as well as intestinal tract act as excretion avenues, consequently lowering the oxalate concentrations within the body. However, oxalate excretion through the kidneys pose risk of toxicological effects on the renal parenchymal cells and of crystal formation in the form of kidney stones. The mammalian intestinal tract thus plays a major role in oxalate control both due to passive and active oxalate transport (Hatch and Freel, 2004; Freel et al., 2006) as well as symbiotic relationships with colonizing oxalate-degrading bacteria.
It has previously been reported that a highly concentrated lyophilized powder containing Oxalobacter formigenes (O. formigenes), a non-pathogenic, obligate anaerobic bacterium that utilizes oxalic acid as its sole source of energy, can be used to decrease oxalate in plasma and urine (U.S. Pat. No. 6,200,562 B1; U.S. Pat. No. 6,355,242 B1). The mechanism for oxalate degradation has been characterized and involves three unique proteins, an oxalate:formate membrane transporter, oxalyl-CoA decarboxylase (OXC), and formyl-CoA transferase (FRC). A very high expression of oxalate degrading proteins and their unique kinetic properties makes O. formigenes one of the most efficient oxalate degrading systems known.
O. formigenes is part of a healthy intestinal microbiota in vertebrates and as such partakes significantly in the oxalate homeostasis process. Mechanistically, O. formigenes increases degradation of oxalate in the gastrointestinal tract, creates a suitable transepithelial gradient, and promotes passive enteric elimination of oxalate. For the skilled artisan the importance of a balanced intestinal microbiota is well known, further, it is also known that developments in the field of microbiology have demonstrated numerous cases of bacterial secretagogue influences in the human intestine. To name a few examples; Vibrio Cholerae and enterotoxigenic Escherichia coli produce secretagogue compounds, which, briefly described, cause an efflux of ions and subsequently fluids into the intestinal lumen with the result of diarrheas (Flores, J., Sharp, G. W., 1976; Field, M., Graf, L. H., et al., 1978). Other intestinal inhabitants induce a hyper-secretion of mucin by secretagogue action (e.g. Navarro-Garcia, F., et al., 2010, Caballero-Franco, C., et al., 2006).
Recently the SLC26 (solute-linked carrier) gene family was identified (Mount, D. B., et al., Pflugers Arch. 2004; 447 (5):710-721; Soleimani, M., Xu, J., Seminars in nephrology. 2006; 26 (5):375-385). This gene family encodes for structurally related anion transporters that have a measurable oxalate affinity and are found in the GI tract: SLC26A1 (SAT1), SCL26A2 (DTDST), SLC26A3 (DRA), SLC26A6 (PAT1 or CFEX), SLC26A7, and SCL26A9. In addition, SLC26A1 and SCL26A2 have been observed in post-confluent and confluent Caco-2 monolayers, respectively (Hatch, M., et al., NIH Oxalosis and Hyperoxaluria Workshop, 2003; Morozumi, M., et al., Kidney Stones: Inside & Out. Hong Kong: 2004, Pp. 170-180). Despite these recent advancement many questions remain on the complex balance of counter ions over the epithelial membrane, the role of different oxalate transporters and what impact they have on hyperoxaluric conditions (Hassan, H. A., Am J Physiol Cell Physiol, 302: C46-058, 2012; Aronson, P. S., J Nephrol 2010; 23 (S16): S158-S164).
Many of the transporters with oxalate affinity also demonstrate affinity for other substrates and often are linked to acid-base balances within the cells; to name a few examples: DRA expressed in Xenopus oocytes is a Cl− base exchanger (Chernova, M. N. et al., J Physiol, 549:3, 2003) and studies suggests SO42− is another substrate (Byeon, M. K. et al., Protein Expr Purif, 12: 67, 1998); mouse PAT-1 expressed in Xenopus exhibits a variety of affinities to Cl−HCO3−, Cl−Ox2−, SO42−Ox2− (Xie Q. et al., Am J Physiol Renal Physiol 283: F826, 2002); and the SLC26A4 gene encodes a Cl− formate exchanger (Morozumi, M. et al. In: Gohel M D I, Au D W T (eds) Kidney stones: inside and out. Hong Kong, p. 170). Many other transporters, without affinity for oxalate, have substrates in common with the oxalate transporting proteins, for example: Na+/K+ ATPase, Na+/H+ exchangers (NHEs), Na+-K+-2Cl− cotransporters (NKCC), and basolateral K+ channels and apical Cl− channels, such as the cystic fibrosis transmembrane conductance regulator (CFTR) (Venkatasubramanian, J. et al., Curr Opin Gastroenterol, 26: 123-128, 2010). The regulation of Na+, Cl−, K+, HCO3− is highly coordinated in the intestinal tract, as it also dictates movement of water, through interactions and regulations of this multitude of transporters outlined.
Several oxalate-reducing pharmaceutical formulations have been described in the art, such as in WO2007070052 A2, Hoppe et al. (Nephrol Dial Transplant, 2011, 26: 3609-3615), and US 20050232901 A1. Among these are enteric coated or other compositions comprising oxalate degrading bacteria or enzymes that have been suggested as a means for reducing oxalate concentrations. An objective with such a treatment is for the patients to get lowered or normalized urinary oxalate levels.
Further, WO2005097176 A2 describes compositions comprising Oxalobacter formigenes, which can be viable and/or a lysate thereof. The compositions are useful for treating an animal subject suffering from renal failure.